The march toward “writing” a complex genome from scratch has taken another step forward, scientists announced on Thursday, with the synthesis of five more of the 16 chromosomes that make up the genome of ordinary brewer’s yeast.
The molecular tricks that scientists learned in making the yeast chromosomes will be useful toward the “Genome Project-Write” — an effort to build synthetic, or lab-made, genomes from off-the-shelf parts, including those of mammals and humans.
“Obviously the details of writing a human genome will be different, but some of the things we learned should feed into GP-Write,” said geneticist Jef Boeke of NYU Langone Medical Center, a co-leader of both the yeast project and GP-Write.
The yeast project announced the completion of its first synthetic yeast chromosome in 2014, and in 2008 other scientists synthesized the first complete bacteria genome. But bacteria genomes are much simpler than yeast’s, making this work the farthest that “synthetic biology” has gotten toward the construction of a genome, the full set of genetic instructions for running its life processes.
Scientists not associated with the yeast research, published in seven papers in Science by more than 200 researchers in four countries, were impressed, with an accompanying commentary calling it “the quintessential first step toward creating a synthetic organism.”
“These are enabling technologies for GP-Write,” said Farren Isaacs, a synthetic biologist at Yale University who is involved in GP-Write but not the yeast project. “The ultimate goal of fully synthetic chromosomes is closer than we once thought.”
The main paper in Science was submitted to the journal in February 2016. In the year it took to coordinate the publication of all seven papers, Boeke said, his lab has synthesized one more yeast chromosome and other labs have also made some. By the end of this year, the Synthetic Yeast 2.0 team hopes to have yeast in which all 16 chromosomes are lab-made.
The ultimate goal of constructing a genome from off-the-shelf building blocks is to make one better than nature did. Harvard biologist George Church, who is also leading GP-Write, has speculated that it might be possible to manufacture a human genome that resists cancer, viral infections, and other scourges. That, however, would require that such a genome replace the original one in, say, a fertilized egg — a step thought to be years if not decades away from scientific feasibility, let alone societal acceptance.
‘Renovating’ the genome
The yeast project, which announced its first synthetic yeast chromosome in 2014, did not create what is now six yeast chromosomes from scratch, if “from scratch” means stringing together, one by one, the thousands of molecules that constitute them. Instead, each team of scientists — Scotland’s University of Edinburgh and the Beijing Genomics Institute did chromosome II, for instance, while Johns Hopkins University did chromosome III — started with pieces 750 base pairs long. (A base pair is one of the A’s, T’s, C’s, or G’s that spell out DNA; the yeast genome is about 12 million base pairs long.)
The scientists stitched those pieces into mini-chunks 2,000 to 3,000 base pairs long, then into mega-chunks up to 60,000 base pairs long. They then swapped the lab-made mega-chunks for the corresponding stretch of a yeast’s natural chromosome, one at a time inside millions of the single-celled organisms. After as many as 33 swaps, the yeast — which readily jettison their own DNA if something new suddenly appears — had a fully synthetic chromosome.
The process was therefore less like building a house from the ground up and more like doing a roof-to-basement renovation, making improvements like replacing Formica countertops with granite ones while the kitchen remained basically intact.
Robust to change
Some yeast eventually contained three synthetic chromosomes. (A molecular “watermark” let the scientists tell lab-made chromosomes from natural ones via DNA sequencing.) For the most part, the organisms functioned fine with them, even when the synthetic chromosomes weren’t exact copies of nature’s.
For instance, the scientists removed superfluous DNA lying within genes (“introns”) and even yanked out one whole group of genes, those that make a molecule called tRNA, from their original chromosomal homes and stuck them into a wholly lab-made chromosome. It was a genetics version of shunting disruptive kids off to the kitchen so the adults could dine in peace: tRNA genes can destabilize a chromosome, said computational biologist Joel Bader of Johns Hopkins University, a co-leader of the yeast project. The scientists therefore gave these genes their own space, a 17th chromosome.
Even with such radical changes, the yeast survived and grew. “Rarely but occasionally, a change caused problems,” Bader said. “But we found ways to fix every problem that cropped up. I certainly did not expect that yeast would turn out to be so robust to change.”
That raises hopes that scientists can make even greater changes, constructing a “designer genome” that might give yeast new traits and capabilities. “We can be even bolder in our future designs,” said Boeke, including “to make the yeast do our bidding and make useful products.”
Yeast (Saccharomyces cerevisiae) are not people, but they are advanced enough to corral their genetic material inside a nucleus, as all animals and plants do. “Having this project succeed tells us how we might proceed in mammals,” Bader said.
Outside scientists agreed. “Is what they did applicable to mammalian genomes? The answer is yes,” said biologist Marc Lajoie of the University of Washington. “The GP-Write team has proposed a number of potential genome design goals, and I don’t think we’re done coming up with ideas yet.”
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